lifelong monitoring of hiv-exposed uninfected infants is...
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Lifelong Monitoring of HIV-Exposed
Uninfected Infants is Jennifer Jao, MD, MPH
Icahn School of Medicine at Mount Sinai
CRUCIAL!
Increasing numbers of HEUs Worldwide
0
200.000
400.000
600.000
800.000
1.000.000
1.200.000
1.400.000
1.600.000
1.800.000
2002 2004 2006 2008 2010 2012
New HIV+ infections in children
HIV+ pregnant women requiring ARVs for PMTCT
UNAIDS 2013: AIDS by the numbers.
Increasing numbers of HEUs Worldwide
0
200.000
400.000
600.000
800.000
1.000.000
1.200.000
1.400.000
1.600.000
1.800.000
2002 2004 2006 2008 2010 2012
New HIV+ infections in children
HIV+ pregnant women requiring ARVs for PMTCT
UNAIDS 2013: AIDS by the numbers.
Do we need long term monitoring of HEUs?
“Follow-up of children with
exposure to ARVs should continue
into adulthood because of the
theoretical concerns regarding the
potential for carcinogenicity of
nucleoside analogue ARV drugs……….
Information regarding such exposure
should be part of ongoing
permanent medical records for
children, particularly those who are
uninfected.” (DHHS Panel on
Treatment of HIV-Infected Pregnant
Women and Prevention of Perinatal
Transmission, 2014)
“Long term follow up of symptomatic children
may be justified and should be guided by best
clinical practices. Families should alert the
child’s physician and/or the physician who
treated the child during the first months of life of
any significant clinical events.” (Medical
Management of Persons Living with HIV, Report
from Expert Panel of CNS and ANRS, 2013)
“…the potential long-term toxicity in healthy exposed
infants and the continuing emergence of new ARVs
make it advisable to devise a mechanism whereby the
identification and registration of potential adverse
long-term effects of such exposures may be
recorded..” (Recommendations by the Spanish Society
of Pediatric Infectious Diseases for the follow up of
the child exposed to HIV and to ARV drugs during
pregnancy and the neonatal period, 2012)
Drug/ Toxin, Stress, Infection
Reorganization/ Adaptation
Cellullar Epigenetic Organ
In utero milieu and Fetal Programming have lasting effects
Risk for Chronic Disease
Later in Life
Maternal Infection Drug/Toxin
Example:
Influenza,
Toxoplasmosis
Example:
Diethylstilbestrol
Metabolic Changes
Example:
IUGR
Schizophrenia
Insulin resistance,
Type 2 DM, CV
Disease Cervical, Vaginal, Breast
Cancer; Infertility
In Utero
HIV/ARV
Exposure
Preterm Birth
SGA
Mitochondrial
Toxicity
Metabolic
Complications?!
Cardiovascular
Disease?!
Mental Health
Problems?!Genotoxicity
Malignancy?!
Neurologic/
Cognitive
Complications?!
Diabetes?!
Poor Bone
Health?!
Short and Long Term Concerns for In Utero HIV/ARV Exposure
Congenital
anomalies
HIV/ARV is associated with Preterm Birth
Authors Cohort Sample size
Finding
Cotter et al 2006 JID U.S. 999 Increased risk with PI vs. non-PI
Sibiude et al 2012 CID French Perinatal Cohort 1253 Increased risk with boosted PI
Lopez et al 2012 AIDS Spain 1557 Increased risk with HIV exposure;
Increased risk with cART
Watts et al 2013 JID PHACS 1869 Increased risk with 1st trimester PI
ECS 2000 AIDS European Collborative
Study and Swiss
Mother+Child Cohort
3920 Increased risk with cART (PI and non-PI
based)
Increased risk with 1st trimester cART
Schulte et al 2007
Pediatrics
U.S. 8793 Increased risk with PI
Townsend et al 2010
BJOG
Pediatric Spectrum of
HIV Disease, European
Collaborative Study,
National Study of HIV in
Pregnancy and
Childhood
19,585 Increased risk with cART
Chen et al 2012 JID Botswana 33,148 Increased risk with HIV exposure;
increased risk with cART
n=19,585
Pediatric Spectrum of HIV Disease, European Collaborative
Study, National Study of HIV in Pregnancy and Childhood
Townsend C et al BJOG 2010
n=19,585
Pediatric Spectrum of HIV Disease, European Collaborative
Study, National Study of HIV in Pregnancy and Childhood
Townsend C et al BJOG 2010
“By the time HEU’s are
diagnosed as HEU’s at 4
months, most of the
significant medical issues
they might have such as
prematurity, low birth
weight, and congenital
defects are already
identified and managed
appropriately.”
SGA/Preterm Birth have long-lasting sequelae:
Adult Metabolic and Cardiovascular Disease
Author Study Finding
Barker et al 1989 Lancet Cohort Low BW associated with death from
ischemic heart disease in adulthood
De Jong et al 2012
Hypertension
Meta analysis Preterm birth and VLBW are
associated with HTN in adulthood
Hofman et al 2006
NEJM
Cohort Preterm birth is associated with
insulin resistance in adulthood
Rotteveel et al 2009
Pediatrics
POPS cohort Preterm birth is associated with
insulin resistance and HTN in
adulthood
Whincup et al 2008 JAMA Pooled
analysis
Lower BW and SGA are associated
with insulin resistance in adulthood
Lawlor et al 2006
Diabetologia
Cohort BW and GA are inversely associated
with diabetes in adulthood
In utero HIV/ARV perturbs intermediary metabolism
DIRECTLY, independent of SGA/ prematurity
Abnormal Fatty-Acid Oxidation in HIV-Exposed Uninfected Neonates in the United States. Kirmse B, Yao T, Hofher S, Williams P, Kacanek D, Hazra R, Borkowsky W, Van Dyke R, Summar M. CROI 2014; Boston.
Preterm Birth is well-documented to cause
neurocognitive sequelae
In Utero HIV/ARV exposure may confer an independent
risk for neurocognitive dysfunction later in life
Preterm Birth is well-documented to cause
neurocognitive sequelae
In Utero HIV/ARV exposure may confer an independent
risk for neurocognitive dysfunction later in life
Preterm Birth is well-documented to cause
neurocognitive sequelae
In Utero HIV/ARV exposure may confer an independent
risk for neurocognitive dysfunction later in life
Preterm Birth is well-documented to cause
neurocognitive sequelae
In Utero HIV/ARV exposure may confer an independent
risk for neurocognitive dysfunction later in life
Not all congenital defects are evident at birth.
Among 12,888 children, 1st
trimester AZT exposure was
significantly associated with
CHD (aOR=2.2; CI=1.3-3.7).
Not all congenital defects are evident at birth.
Among 12,888 children, 1st
trimester AZT exposure was
significantly associated with
CHD (aOR=2.2; CI=1.3-3.7).
In utero HIV/ARV is associated with
mitochondrial toxicityAuthors Study Sample
sizeFindings
Poirier et al 2003 WITS 30 Decreased mtDNA
Ross et al 2011 U.S. 46 Abnormal mtDNA levelsDecreased Complex II:IV
Gingelmaier et al 2009
Germany 77 Decreased mtDNADecreased Complex II:IV
Aldrovandi et al 2010
WITS, PACTG 1009
624 Abnormal mtDNA levels
Côté et al 2008 Canada 154 Increased mtDNA levelsAbnormal mitochondrial gene expression
McComsey et al 2008
ACTG 5084 136 Increased mtDNA levels
Torres et al 2009 U.S. 108 Increased mitochondrial mutations
In utero HIV/ARV is Associated with Clinically
Significant Mitochondrial Dysfunction
18 month incidence of
neuro-mitochondrial
disease was 0.26% (95% CI:
0.10 – 0.54) in HIV-exposed
children compared to 0.01%
in the general pediatric
population
In utero tenofovir exposure affects
postnatal growth and bone mineral content
CID June 2015 epub print
HEU’s have high rates of mental health problems
Mental health problems were
more prevalent in HEU children
than HIV-infected children
(38 vs. 25%, p<0.01) in the PHACS
cohort
Amongst HEUs, the prevalence
of any psychiatric disorder (57%)
remained high and mood
disorders INCREASED (4.4-8.8%,
p<0.05) over time compared to
HIV-infected children in the
CASAH cohort.
Both AZT and TDF confer genotoxicity
Elevations in GPA
N/N variants
persisted even up
to 1 year of age.
Both AZT and TDF confer genotoxicity
Frequency of aneuploidy
was significantly higher
with AZT exposure, but
both AZT and TDF
exhibited altered gene
expression for DNA repair
and telomere maintenance
pathways.
p<0.05
“Lifelong follow-up will
increase stigma to HEU
infants.”
Stigma is a small price to pay if lifelong
follow-up uncovers a serious late
adverse effect of in utero HIV/ARV
exposure!
“Lifelong follow up may not be
warranted in all settings. With
the scale up of PMTCT and
Pediatric ART programs there are
already competing resources in
resource-limited settings.”“Given that the HIV burden in women is greatest in
resource-constrained countries where rapid expansion in ARV
use in pregnancy is expected with implementation of WHO
guidelines, there is an ethical imperative to systematically
and critically evaluate the safety of these recommendations
for the fetus/infant both in terms of potential
teratogenicity but also long term outcomes.”
Mofenson LM & Watts DH. 2014. PLOS Medicine
Vote YES! for long term follow up of HEUs
Si!
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kyllä
نعم
THANK YOU!
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